This invention relates to novel compositions useful for the sustained-release of bioactive proteins. More particularly, the present invention provides a superior aqueous sustained release injectable formulation of bovine growth hormone releasing factor. Also provided are methods of using these novel compositions for the sustained or prolonged release of bovine growth hormone releasing factor.
With the advent of genetic engineering, the large-scale availability of many bioactive peptides and proteins has been achieved. However, the administration of these recombinantly produced peptides and proteins presents a unique set of problems. In many cases the maintenance of the biological effect of these proteins requires long-term administration. Since daily administration of these agents is inconvenient, sustained or prolonged release is preferred.
For numerous reasons, the art has long focused on the use of biocompatible oils as vehicles to achieve the sustained release of many drugs, including proteins and specifically somatotropins. Among the patents directed to this technology are U.S. Pat. No. 5,013,713 to Mitchell and U.S. Pat. No. 4,977,140 to Ferguson et al. Mitchell reports that prolonged parenteral release of bovine somatotropin (bSt;BGH) at desirably effective levels can be achieved using substantially non-aqueous compositions comprising at least about 10% by weight of a biologically active somatotropin and, as a continuous phase of the composition, a biocompatible oil such as corn oil. Ferguson et al. report that the injection of a sustained release formulation comprising bSt, wax and an oil increases daily milk production in a cow for an extended period of time.
Those skilled in the art have also directed their attention to achieving the sustained release of other growth enhancing proteins such as growth hormone releasing factor. Specifically, U.S. Pat. No. 5,352,662 to Brooks et al. reports an injectable, extended release formulation which includes a growth hormone or a growth hormone releasing factor in a carrier including a biocompatible hydrophobic vehicle and an amount of polyglycerol ester effective to extend release of the proteins in the animal.
The above patents illustrate the art's emphasis on the use of non-aqueous delivery systems for the prolonged release of growth hormones and growth hormone releasing factors. Recently, the art has taught the use of an aqueous formulation to achieve the prolonged release of bSt. International Pat. No. Application No. PCT/US95/00023 teaches the prolonged parenteral release into the circulatory system of a cow of a bioactive bSt. This is achieved by using novel compositions in which the bSt is present in an aqueous liquid at a dose of at least about 150 mg and at a concentration of at least about 50 mg/ml. The disclosed aqueous bSt formulation reportedly provides for the sustained release of bSt into the circulatory system of the animal for greater than 3 days.
Prior to this teaching, however, the art studiously avoided using aqueous systems for the sustained delivery of proteins, especially somatotropins. The reason for this behavior was the general view that proteins are highly unstable when exposed to aqueous environments for long periods of time. (Pitt, Int. J. Pharmaceutics 59:173-196 (1990)). As different proteins behave differently in aqueous environments (bSt comprises 191 amino acids whereas growth hormone releasing factors comprises 44 amino acids), the general view of the art that proteins are highly unstable when exposed to aqueous environments for long periods of time remains uncontradicted for growth hormone releasing factor.